1. Field of the Invention
The present invention relates in general to nano- and micro-structured vesicles having a novel bilayer membrane formed using branched, amphipathic peptides.
2. Description of the Prior Art
Since many drugs are rapidly destroyed or inactivated when introduced to the body, various strategies have been developed to improve delivery and increase the biological half-life of the bioactive materials. Current drug delivery methodologies that address these issues rely on several biomaterials as well as some inorganic molecules. Some of these materials include polyethylene glycol, micelles, lipid vesicles, viral capsids, and nanoparticles. More recently, peptide vesicles have been developed for drug delivery methods. As used herein, the term “peptide vesicle” includes small membrane enclosed sacs, usually containing liquid or gas, formed from block copolymers or block copolypeptides (when amino acids are used) and is used interchangeably with polymersomes, polymer vesicles, peptosomes, and oligo- or polypeptide vesicles.
Existing methodologies for preparing peptide vesicles include the use of various diblock or triblock copolymers, where blocks of hydrophobic and hydrophilic amino acids (in their natural or modified forms) are linearly copolymerized. Block copolymer amphiphiles are polymers that are composed of segments of repeating units covalently linked together wherein the segments can have different properties to give the polymer an amphiphilic nature. The ability of diblock copolymers to possess both a hydrophobic and hydrophilic block gives these polymers a lipid-like character, yet with greater stability than their lipid counterparts. These blocks in block copolymers can be synthetic, semisynthetic or, as recently shown, composed entirely of biological building blocks like amino acids. Amino acid block copolymers can range anywhere from 30aa to 120aa or more, and like other block copolymers are capable of self-assembling into micelles, vesicles, bilayers or other ordered structures. These assemblies require the peptides to adopt a helical structure in their final assembled structure. Existing reported structures have been generated from linear block polypeptides and have characteristics similar to lipids.
More recently, polypeptide vesicles have been formed from copolypeptides of the type KxLy, ExLy and RxLy, where K is lysine, L is leucine, E is glutamic acid, and R is arginine, and where x can range up to 60 units and y up to 20 units. These copolypeptides have been shown to form various structures including micelles, vesicles and vesicle-inside-vesicles. They have shown that in general, the shape and size of the structures formed can be controlled by varying the hydrophobicity or the overall chain length of the polypeptide. Others have tried synthesizing copolymers/copolypeptides to develop vesicles that can act as biomimetic encapsulants. Examples include: poly (styrene)-b-poly(acrylamide); poly (styrene)-b-poly(isocyanide) copolymers; EO40-EE37(polyethylene oxide-polyethylenethylene); PB40-b-PGA100 poly (butadiene)-b-poly(γ-L-glutamic acid); glycine based peptides (G4D2, G6D2, G8D2, G10D2); K100L20; K60L20; H-Glu-ΔPhe-OH and H-Lys-ΔPhe-OH Amphiphilic dipeptides; and poly (sarcosine)-poly(γ-L-glutamic acid).
Although, it is usually considered that polymersomes formed from block copolymers are high in molecular weight (MW>>10 kDa), the simplest unit so far mentioned in literature involved in the formation of vesicles that can act as a encapsulant is a dipeptide.